Peripheral arterial disease (PAD) impairs arterial blood flow to the legs & is a major indicator of systemic atherosclerosis. PAD affects 5% of the US population over 50. Approx 1/3 of patients with PAD have typical claudication, defined as pain in one or both legs on walking, that is relieved by rest. Patients with claudication have a marked impairment in exercise performance similar to patients with NYHA class III heart failure. Goals of treatment for PAD patients include risk-factor modification & antiplatelet drug therapy to address increased cardiovascular mortality risk. Supervised exercise training is the most efficacious treatment to improve walking capacity, demonstrated in many (small) randomized trials. Neither the pathophysiology of claudication nor the mechanism(s) by which exercise training improves walking times in persons with IC are completely understood. It is unknown how long-term exercise training affects skeletal muscle or to what extent skeletal muscle abnormalities in PAD are reversible. Women have been largely underrepresented in mechanistic studies of IC and exercise training. There is an urgent need for clinical research directed towards defining the basis of the exercise training changes induced in PAD patients in order to: 1) provide insights into the general pathophysiology of the exercise impairment in PAD; 2) permit scientifically plausible & testable modifications to currently prescribed exercise regimens to better employ this critical therapeutic modality &, 3) identify novel targets from pharmacotherapy that are capable of inducing the repertoire of molecular responses induced by exercise training. In this RFA (HL-03-003) (AMNESTI in PAD), men & women (n=160), over 40 years, with IC & an ankle/brachial systolic blood pressure ratio (ABI) <0.8 at rest, will be recruited from Duke Univ Med Ctr and the Univ of Colorado Health Sci Ctr. Patients will be randomized to a supervised or home-based exercise program. Evaluations will be at baseline, 3-weeks (super vised exercise) and 3-months. Age-gender matched healthy controls (n=66) will be tested at base line. The central hypothesis is that the beneficial effects of exercise training are primarily mediated through an angiogenic effect. Sp Aim 1 will establish the baseline vascular abnormalities present in patients. Sp Aim 2 will establish the ability of the selected vascular abnormalities in Sp Aim I to pre- dict peak oxygen consumption in PAD using a prediction model. Sp Aim 3 will establish the ability of exercise training to modify the vascular abnormalities in PAD. Sp Aim 4 will examine the gender specificity of the results obtained in Sp Aim 1-3.